We have previously characterized a deficit in sensory gating in schizophrenic patients. The P50 auditory evoked potential wave is decremented in response to the second of closely paired stimuli in most normals, but not in most schizophrenics. This failure in auditory sensory gating is a familial trait that also is found in about half the first degree relatives of schizophrenics. Pyramidal neurons of the CA3 layer of rat hippocampus have similar gated responses that may serve as an animal model for neurobiological studies of this phenomenon. The objectives of the present proposal are: (1) to determine why some family members with deficits in sensory gating are clinically ill, while most are not; (2) to characterize the pharmacology of deficits in sensory gating in schizophrenics and their relatives; and (3) to investigate further the cellular neurobiology of sensory gating in animal models. For objective (1), we will continue a multiparameter comparison of schizophrenics and their siblings. We will use magnetic resonance imaging to further test our initial finding that the left anterior hippocampus is smaller in schizophrenics, compared to their siblings with sensory gating deficits. For objective (2), we will pursue a preliminary finding of the role of nicotinic cholinergic neurotransmission in the sensory gating deficit, by assessing the ability of cholinergic agents to reverse sensory gating deficits in schizophrenics and their siblings. For objective (3), we will use a newly developed strategy for multiple simultaneous single neuron recordings from neural networks and other neurobiological techniques in rats to describe the neuronal pathways responsible for sensory gating. We will continue our investigation of sensory gating in the pontine reticular formation, which may influence sensory gating in the hippocampus, via the medial septal nucleus. The three objectives are designed to increase basic knowledge of the neuronal basis of sensory gating (aim 3), to assess which neuronal mechanisms may be deficient in schizophrenics and their relatives (aim 2), and to determine under what conditions individuals with a deficit in sensory gating become ill with schizophrenia (aim 1).